Hypoxia-induced Responses and Innate Immunity

巨噬细胞和中性粒细胞作为先天免疫系统的组成部分，对于对感染的即时反应是必不可少的，这些细胞通常在微生物，特别是细菌感染期间在低氧的微环境中发挥作用。我们的目标是通过研究缺氧诱导的转录因子HIF-1a在这一过程中的作用，来确定髓系细胞在细菌攻击过程中的缺氧反应机制。该提案的具体目的是：具体目标1：确定HIF-1a在调节髓系细胞的微生物杀伤功能中的作用；1a。分析常氧、低氧和缺氧条件下HIF-1a在中性粒细胞和巨噬细胞杀菌中的作用；确定HIF-1a在HIF-1中的作用 中性粒细胞和巨噬细胞产生的氧化性突发性和反应性氮； 确定HIF-1a在中性粒细胞蛋白水解酶活性和中性粒细胞抗菌肽的产生和激活中的作用；特异性目标2：确定HIF-1a在髓系细胞迁移、存活和免疫激活功能中的作用；2a。分析常氧、低氧和缺氧条件下HIF-1a在中性粒细胞趋化和内皮细胞转运中的作用；确定HIF-1a在保护中性粒细胞和巨噬细胞免受细菌诱导的细胞毒性和凋亡中的作用；确定HIF-1a在中性粒细胞和巨噬细胞对细菌刺激反应的促炎细胞因子基因激活模式中的作用；特定目标3：确定HIF-1a在天然免疫中的作用 体内细菌感染的防御；3a。使用小鼠皮下组织笼模型确定HIF-1a在局部中性粒细胞迁移和杀伤中的作用；3b。使用小鼠皮下感染模型确定HIF-1a在限制从缺氧灶全身传播感染中的作用！使用小鼠静脉感染模型确定HIF-1a在细菌败血症的发生和控制中的作用。

Macrophage and neutrophils are essential for an immediate response to infection as components of the innate immune system, and these cells often function in a hypoxic micro-environment during microbial, and especially bacterial, infection. Our goal is to determine the mechanisms of hypoxic response in myeloid cells during bacterial challenge, through studying the role of the hypoxia-induced transcription factor HIF-1a during that process. The specific aims of this proposal are: Specific aim 1: Determine the role of HIF-1a in regulating the microbial killing functions of myeloid cells; 1a. Analyze the role of HIF-1a in neutrophil and macrophage bacterial killing under normoxic, hypoxic and anoxic conditions; 1b. Determine the role of HIF-1a in neutrophil and macrophage production of the oxidative burst and reactive nitrogen species; 1c. Determine the role of HIF-1a in neutrophil protease activity and the production and activation of cathelicidin antimicrobial peptides; Specific aim 2: Determine the role of HIF-1a in the migratory, survival and immune-activating functions of myeloid cells; 2a. Analyze the role of HIF-1a in neutrophil chemotaxis and endothelial transcytosis under normoxic, hypoxic and anoxic conditions; 2b. Determine the role of HIF-1a in protection of neutrophils and macrophages against bacterial-induced cytotoxicity and apoptosis; 2c. Determine the role of HIF-1a in the pattern of proinflammatory cytokine gene activation in neutrophils and macrophages responding to a bacterial stimulus; Specific aim 3: Determine the function of HIF-1a in innate immune defense against bacterial infection in vivo; 3a. Determine the role of HIF-1a in localized neutrophil migration and killing using a murine subcutaneous tissue cage model; 3b. Determine the role of HIF-1a in restricting systemic spread of infection from a hypoxic focus using a murine subcutaneous infection mode!; 3c. Determine the role of HIF-1a in development and control of bacterial septicemia using a murine intravenous infection model.